Voltage-gated potassium channels regulate the electrical activity of excitable cells, such as nerve and muscle cells, by gating open a potassium channel conductance in response to increased electrical activity in the cell. Because potassium is high inside the cell, the loss of potassium ions through this pore makes the inside of the cell more negative, inhibiting further electrical activity. Problems in potassium channels have been linked to numerous diseases, including: cardiac arrhythmias, epilepsy, and electrical rhythm disturbances. Drugs targeting potassium channels are used to treat a variety of disorders including hypertension, multiple sclerosis, and diabetes. In addition, the structure of potassium channels are similar to other ion channels, such as sodium and calcium channels. In this study we are continuing our investigation into the question of what unique properties are encoded in the different families of potassium channels. These studies are revealing how specific domains on the cytoplasmic surfaces of the channels are involved in the regulation of channel assembly, function, and the interactions with other cellular signaling systems. In Specific Aim 1, we will continue our studies determining the structures of these channels by completing the structural determination of the cytoplasmic N-terminus of a Shaker type potassium channel, and determining how other proteins interact with this structure. In Specific Aim 2, we will move our focus to the full length channel to determine how the cytoplasmic N-terminus is integrated into the full channel, and whether the structure of the cytoplasmic N-terminus is coupled to channel gating status. Finally,. In Specific Aim 3 will examine what the role of Zn2+ ions is in non-Shaker type potassium channels. The presence of a structural Zn2+ ion is one striking difference between non-Shaker potassium channels and Shaker type channels. Our studies will determine what the role of this Zn2+ ion is in these channels. By completing these studies we will significantly extend our understanding of the structures of voltage-gated potassium channels, and their roles as part of the cell biology of excitable cells.